CN103819471A - Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof - Google Patents

Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof Download PDF

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CN103819471A
CN103819471A CN201310606201.1A CN201310606201A CN103819471A CN 103819471 A CN103819471 A CN 103819471A CN 201310606201 A CN201310606201 A CN 201310606201A CN 103819471 A CN103819471 A CN 103819471A
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derivative
pyrimidine
pyrido
drugs
phenyl
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陈兴海
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ZHENJIANG SHENG'AN PHARMACEUTICAL CO Ltd
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ZHENJIANG SHENG'AN PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention discloses a derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and an application thereof. The derivative has good pharmaceutical activity, can greatly prolong the half-life periods of drugs, prolongs the retention time of drugs in the human body, and meanwhile increases the drug concentration in the blood. Therefore, a better curative effect is achieved. As the half-life periods of drugs are greatly prolonged, the drugs can keep activity concentration for a longer time in the blood. Under the cure condition with dose limiting, the curative effect can be kept and the recommended dosage of drugs can be reduced at the same time, therefore the bad metabolism of drugs is eliminated, the drug toxicity is reduced, and the toxic and side effects in the drug using process are small.

Description

Derivative and the application thereof of pyrido (4,3-d) pyrimidine-1 (2H)-Ji phenyl-acetamides
Technical field
The present invention relates to a kind of derivative and application thereof of compound, belong to technical field of pharmaceuticals.
Background technology
Melanoma is the malignant tumour that a kind of grade malignancy is quite high, claims again melanotic sarcoma, is mostly primary in skin, also can originate from eye, nasal cavity etc. and locate, and can shift in early days the common lung of metastasis site, brain.Melanoma is in dermatosis, to cause dead topmost sick kind.National Cancer Institute estimates to have for 2013 nearly 76690 Americans to be diagnosed as melanoma, and has 9480 to die from this kind of disease.On May 29th, 2013, U.S. food Drug Administration (FDA) has ratified a kind of new drug and has been used for the treatment of metastasis melanin tumor and melanoma patient that can not row operative treatment, and whether the use of this new drug simultaneously also can be used for diagnosing this patient to be applicable to receiving treatment.The chemical name of this new drug is: the fluoro-4-iodophenyl of N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide.Trade name: Sibutramine Hydrochloride is for Buddhist nun (Trametinib).This medicine is a kind of extracellular signal-regulated kinase inhibitor (mek inhibitor).Be used for the treatment of metastasis melanin tumor and melanoma patient that can not row operative treatment.Sibutramine Hydrochloride is to promote mitogen activation for Buddhist nun's mechanism of action, is a kind of extracellular signal-regulated kinase inhibitor (mek inhibitor).Find in Buddhist nun's clinical experimental study at Sibutramine Hydrochloride, compared with chemotherapy, Sibutramine Hydrochloride has significantly improved patient's Progression free survival phase and Overall survival for Buddhist nun.Due in the time using Sibutramine Hydrochloride to treat for Buddhist nun; conventionally strengthen dosage in order to reach result for the treatment of; cause producing a lot of poor metabolism problems; the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects; thereby can produce a lot of toxic side effect to human body in therapeutic process; patient in treatment there will be untoward reaction in various degree conventionally, and the most serious untoward reaction comprises: cardiac failure, pneumonia, skin infections, blind.Modal untoward reaction comprises: fash, diarrhoea, swollen tissue (PE), acne sample skin dermexanthesis.Simultaneously FDA points out that Women of Childbearing Age uses Sibutramine Hydrochloride to have the risk that causes fetus infringement for Buddhist nun, and male patient and female patients use this kind of medicine to have to cause infertile risk.Women should be confirmed whether gestation for before Buddhist nun treatment accepting Sibutramine Hydrochloride, and men and women patient all should be warned these risks and need to take birth-control measures.
Summary of the invention
The object of the invention is to overcome defect of the prior art, pyrido (4,3-d) pyrimidine-1(2H is provided) derivative and the application thereof of-Ji phenyl-acetamides, the pharmaceutical activity of described derivative is good, the bad metabolic problems that can solve medicine simultaneously, the toxic side effect in medication process is little.
The present invention is achieved by the following technical programs.
Pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, there is the following chemical structure general formula:
Figure DEST_PATH_GDA0000479559160000021
R in formula 1, R 2, R 3be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R 1, R 2, R 3in one or several is fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R 1, R 2, R 3be fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R 1, R 2, R 3in one or several is deuterium.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R 1, R 2, R 3be deuterium.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) application of derivative of-Ji phenyl-acetamides, the application of described derivative in the medicine of preparation treatment metastasis melanin tumor and melanoma disease that can not row operative treatment.
Pyrido (4 of the present invention, 3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides can be used as the activeconstituents of the medicine for the treatment of metastasis melanin tumor and melanoma disease that can not row operative treatment, in this medicine, also can contain described derivative and pharmaceutically acceptable carrier or the figuration body of significant quantity, make the formulation that is applicable to use.Drug delivery system can be albumin bound type injection liquid, liposome, powder pin, nanoparticle and cyclodextrin inclusion compound etc., form of administration can be injection liquid, also can be solid dosage or semisolid dosage form, as being injection, tablet, wafer, pill, powder or granule etc.
Pyrido (4 of the present invention, 3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides can be made into the pharmaceutically acceptable salt that is suitable as medicine, the pharmaceutically acceptable salt that is suitable as medicine refers to the salt that is suitable as medicine that compound of the present invention and acid or alkali form, and comprises inorganic salt and organic salt.The preferred salt of one class is compound of the present invention and the sour salt forming.The acid that is applicable to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, benzene methanesulfonic acid and Phenylsulfonic acid; And the acidic amino acid such as aspartic acid, L-glutamic acid.
Pyrido of the present invention (4,3-d) pyrimidine-1(2H) derivative and the Sibutramine Hydrochloride of the prior art of-Ji phenyl-acetamides is for compared with Buddhist nun, and tool has the following advantages:
(1) better efficacy of derivative of the present invention, it can increase the transformation period of medicine greatly, the time that prolong drug is detained at human body Inner, improves the concentration of blood Chinese traditional medicine simultaneously, thereby reaches better curative effect.
(2) the drug use dosage of derivative of the present invention is less, thereby can eliminate the bad metabolic problems of medicine, because the transformation period of medicine greatly increases and makes medicine can keep for more time active concentration in blood, make under the treatment condition that has dose limitation, the using dosage that can reduce medicine in keeping curative effect, reduces drug toxicity.
(3) toxicity of derivative of the present invention, side effect are still less, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, eliminate the bad metabolic problems of medicine, greatly reduced toxicity and other side effects of medicine.
Embodiment
By specific embodiment, the specific embodiment of the present invention is described in further detail below.
Embodiment 1
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.
Synthetic reduction and 2 steps of acetylize of comprising of derivative of the present invention:
Preparation process is as follows:
(1) reduction step
Preparation [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2, reaction equation is as follows:
Figure DEST_PATH_GDA0000479559160000051
Under anhydrous and oxygen-free argon shield; in dry three-necked flask, add [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6 of 3.78 grams; 8-dimethyl-1-(3-nitrophenyl)-pyrido [4; 3-d] pyrimidine-2; 4; the methylene dichloride of 7 (1H, 3H, 6H)-triketone 1-1 and 40ml.Under stirring at room temperature, add the sodium bisulfite of 3.27 grams and the water of 2 milliliters, stirring reaction 3-5 hour, temperature of reaction 80-95 ℃, then adds the water of 120 milliliters.Precipitation, separates, and washing can obtain [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2.
(2) acetylize step
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.
Figure DEST_PATH_GDA0000479559160000061
Under anhydrous and oxygen-free argon shield; in dry flask, incite somebody to action [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6; 8-dimethyl-1-(3-aminophenyl)-pyrido [4; 3-d] pyrimidine-2,4,7 (1H; 3H; 6H)-triketone 1-2 is suspended in pyridine and trichloromethane, adds acetic acid-d3 acid anhydride, stirring reaction 1-3 hour under stirring at room temperature.With the hydrochloric acid soln cancellation reaction of 1 volumetric molar concentration, then add trichloromethane.Organic phase is used respectively saturated common salt water washing.Anhydrous sodium sulfate drying.Filter, concentrated.Thick product obtains the fluoro-4-iodophenyl of target product N-[3-[3-cyclopropyl-5-[(2-through purification by silica gel column chromatography) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.[the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4, the mole ratio of 7 (1H, 3H, 6H)-triketone 1-2 and acetic acid-d3 acid anhydride is 1 ︰ 1-1.2.1 molar [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2 uses hydrochloric acid, the trichloromethane of 5-10L and the saturated aqueous common salt of 10-40L of 1 volumetric molar concentration of pyridine, the 20-40L of 2-5L.
Embodiment 2
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1-d1.
Figure DEST_PATH_GDA0000479559160000071
Preparation method, with embodiment 1, replaces with acetic acid-d2 acid anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 3
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1-d2.
Figure DEST_PATH_GDA0000479559160000072
Preparation method, with embodiment 1, replaces with acetic acid-d1 acid anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 4
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1,1,1-trifluoroacetamide.
Figure DEST_PATH_GDA0000479559160000081
Preparation method, with embodiment 1, replaces with 1,1,1-trifluoro-acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 5
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1,1-bis-monofluoroacetamides.
Figure DEST_PATH_GDA0000479559160000082
Preparation method, with embodiment 1, replaces with 1,1-difluoro acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 6
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1-monofluoroacetamide.
Figure DEST_PATH_GDA0000479559160000091
Preparation method, with embodiment 1, replaces with 1-fluorine acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Here description of the invention and application is illustrative, not wants scope of the present invention to limit in the above-described embodiments, and therefore, the present invention is not subject to the restriction of the present embodiment, and the technical scheme that any employing equivalence replacement obtains is all in the scope of protection of the invention.

Claims (6)

1. pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that thering is the following chemical structure general formula:
Figure DEST_PATH_FDA0000479559150000011
R in formula 1, R 2, R 3be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
2. pyrido as claimed in claim 1 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R 1, R 2, R 3in one or several is fluorine.
3. pyrido as claimed in claim 2 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R 1, R 2, R 3be fluorine.
4. pyrido as claimed in claim 1 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R 1, R 2, R 3in one or several is deuterium.
5. pyrido as claimed in claim 4 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R 1, R 2, R 3be deuterium.
6. the pyrido (4 as described in any one in claim 1-5,3-d) pyrimidine-1(2H) application of derivative of-Ji phenyl-acetamides, it is characterized in that the application of described derivative in the medicine of preparation treatment metastasis melanin tumor and melanoma disease that can not row operative treatment.
CN201310606201.1A 2013-11-25 2013-11-25 Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof Pending CN103819471A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320513A (en) * 2018-11-09 2019-02-12 安庆奇创药业有限公司 A method of synthesis Trimetinib
EP4087868A4 (en) * 2020-01-08 2024-03-20 Icahn School of Medicine at Mount Sinai Small molecule modulators ksr-bound mek

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012088033A2 (en) * 2010-12-20 2012-06-28 Glaxosmithkline Llc Novel pharmaceutical composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012088033A2 (en) * 2010-12-20 2012-06-28 Glaxosmithkline Llc Novel pharmaceutical composition

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320513A (en) * 2018-11-09 2019-02-12 安庆奇创药业有限公司 A method of synthesis Trimetinib
CN109320513B (en) * 2018-11-09 2021-03-16 安庆奇创药业有限公司 Method for synthesizing trametinib
EP4087868A4 (en) * 2020-01-08 2024-03-20 Icahn School of Medicine at Mount Sinai Small molecule modulators ksr-bound mek

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Application publication date: 20140528